G. Taccetti

European Cystic Fibrosis Society Standards of Care: Best Practice guidelines.

Specialised CF care has led to a dramatic improvement in survival in CF: in the last four decades, well above what was seen in the general population over the same period. With the implementation of newborn screening in many European countries, centres are increasingly caring for a cohort of patients who have minimal lung disease at diagnosis and therefore have the potential to enjoy an excellent quality of life and an even greater life expectancy than was seen previously. To allow high quality care to be delivered throughout Europe, a landmark document was published in 2005 that sets standards of care. Our current document builds on this work, setting standards for best practice in key aspects of CF care. The objective of our document is to give a broad overview of the standards expected for screening, diagnosis, pre-emptive treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support. For comprehensive details of clinical care of CF, references to the most up to date European Consensus Statements, Guidelines or Position Papers are provided in Table 1. We hope that this best practice document will be useful to clinical teams both in countries where CF care is developing and those with established CF centres.

Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients

In cystic fibrosis (CF) patients early antibiotic treatment of lung infection has been shown to lead to Pseudomonas aeruginosa eradication. The present study determined: 1) the time period from eradication to new P. aeruginosa acquisition; 2) P. aeruginosa re-growth and new acquisition; and 3) the impact of eradication therapy on lung function, antimicrobial resistance, emergence of other pathogens and treatment costs. Ciprofloxacin and colistin were used to eradicate P. aeruginosa in 47 CF patients. Bacterial pathogens, lung function decline, P. aeruginosa antimicrobial resistance and anti-pseudomonal serum antibodies were assessed quarterly and compared with an age-matched CF control group. Additionally, costs of antibiotic therapy in both groups were assessed. Early antibiotic therapy leads to a P. aeruginosa free-period of a median (range) of 18 (4–80) months. New acquisition with different P. aeruginosa genotypes occurs in 73% of episodes. It also delays the decline of lung function compared with chronically infected patients, prevents the occurrence of antibiotic resistant P. aeruginosa strains, does not lead to emergence of other pathogens, and significantly reduces treatment costs. The treatment substantially lowers P. aeruginosa prevalence in CF. In conclusion, early antibiotic therapy exerts beneficial effects on the patients clinical status and is cost-effective compared with conventional antibiotic therapy for chronically infected cystic fibrosis patients.

Early antibiotic treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: a randomised multicentre study comparing two different protocols

Background Pseudomonas aeruginosa chronic pulmonary infection is an unfavourable event in cystic fibrosis. Bacterial clearance is possible with an early antibiotic treatment upon pathogen isolation. Currently, no best practice exists for early treatment. The efficacy of two different regimens against initial P aeruginosa infection was assessed. Methods In a randomised, open-label, parallel-group study involving 13 centres, the superiority of inhaled tobramycin/oral ciprofloxacin compared with inhaled colistin/oral ciprofloxacin (reference treatment) over 28 days was evaluated. Patients were eligible if they were older than 1 year with first or new P aeruginosa isolation. Treatments were assigned equally by centralised balanced randomisation, stratified by age and forced expiratory volume in 1 s values. The participants and those giving the intervention were not masked to arm assignments. The primary endpoint was P aeruginosa eradication, defined as three successive negative cultures in 6 months. Analysis was by intention to treat. This trial was registered with EudraCT, number 2008-006502-42. Results 105 patients were assigned to inhaled colistin/oral ciprofloxacin (arm A) and 118 to inhaled tobramycin/oral ciprofloxacin (arm B). All patients were analysed. P aeruginosa was eradicated in 66 (62.8%) patients in arm A and in 77 (65.2%) in arm B (OR 0.90, 95% CI 0.52 to 1.55, p=0.81). Following treatment, an increase in Stenotrophomonas maltophilia was noted (OR 3.97, 95% CI 2.27 to 6.94, p=0.001) with no differences between the two arms (OR 0.89, 95% CI 0.44 to 1.78, p=0.88). Conclusions No superiority of treatment under study was demonstrated in comparison to the reference treatment. Early eradication treatment was associated with an increase in S maltophilia.

Emended description of mycobacterium abscessus mycobacterium abscessus subsp. Abscessus and mycobacterium abscessus subsp. bolletii and designation of mycobacterium abscessus subsp. massiliense comb. nov.

The taxonomic position of members of the Mycobacterium abscessus complex has been the subject of intensive investigation and, in some aspects confusion, in recent years as a result of varying approaches to genetic data interpretation. Currently, the former species Mycobacterium massiliense and Mycobacterium bolletii are grouped together as Mycobacterium abscessus subsp. bolletii. They differ greatly, however, as the former M. bolletii has a functional erm(41) gene that confers inducible resistance to macrolides, the primary therapeutic antimicrobials for M. abscessus, while in the former M. massiliense the erm(41) gene is non-functional. Furthermore, previous whole genome studies of the M. abscessus group support the separation of M. bolletii and M. massiliense. To shed further light on the population structure of Mycobacterium abscessus, 43 strains and three genomes retrieved from GenBank were subjected to pairwise comparisons using three computational approaches: verage ucleotide dentity, enome to enome istance and single nucleotide polymorphism analysis. The three methods produced overlapping results, each demonstrating three clusters of strains corresponding to the same number of taxonomic entities. The distances were insufficient to warrant distinction at the species level, but met the criteria for differentiation at the subspecies level. Based on prior erm(41)-related phenotypic data and current genomic data, we conclude that the species M. abscessus encompasses, in adjunct to the presently recognized subspecies M. abscessus subsp. abscessus and M. abscessus subsp. bolletii, a third subspecies for which we suggest the name M. abscessus subsp. massiliense comb. nov. (type strain CCUG 48898T=CIP 108297T=DSM 45103T=KCTC 19086T).

Transmission of Burkholderia cepacia Complex: Evidence for New Epidemic Clones Infecting Cystic Fibrosis Patients in Italy

ABSTRACT To analyze national prevalence, genomovar distribution, and epidemiology of the Burkholderia cepacia complex in Italy, 225 putative B. cepacia complex isolates were obtained from 225 cystic fibrosis (CF) patients attending 18 CF centers. The genomovar status of these isolates was determined by a polyphasic approach, which included whole-cell protein electrophoresis and recA restriction fragment length polymorphism (RFLP) analysis. Two approaches were used to genotype B. cepacia complex isolates: BOX-PCR fingerprinting and pulsed-field gel electrophoresis (PFGE) of genomic macrorestriction fragments. A total of 208 (92%) of 225 isolates belonged to the B. cepacia complex, with Burkholderia cenocepacia as the most prevalent species (61.1%). Clones delineated by PFGE were predominantly linked to a single center; in contrast, BOX-PCR clones were composed of isolates collected either from the same center or from different CF centers and comprised multiple PFGE clusters. Three BOX-PCR clones appeared of special interest. One clone was composed of 17 B. cenocepacia isolates belonging to recA RFLP type H. These isolates were collected from six centers and represented three PFGE clusters. The presence of insertion sequence IS1363 in all isolates and the comparison with PHDC reference isolates identified this clone as PHDC, an epidemic clone prominent in North American CF patients. The second clone included 22 isolates from eight centers and belonged to recA RFLP type AT. The genomovar status of strains with the latter RFLP type is not known. Most of these isolates belonged to four different PFGE clusters. Finally, a third clone comprised nine B. pyrrocinia isolates belonging to recA RFLP type Se13. They represented three PFGE clusters and were collected in three CF centers.

Antibiotic Therapy against Pseudomonas aeruginosa in Cystic Fibrosis

Abstract Antibiotic strategies against Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients should consider the natural history of the P. aeruginosa infection, ranging from the first isolation of the germ in the airways to isolation at every microbiological culture, and the patients clinical condition. Antibiotic treatment against P. aeruginosa given at the time of first isolation may prevent or delay chronic infection. The period of intermittent colonization can be considered the time before the development of mucoid P. aeruginosa phenotype. The optimal treatment strategy in this stage remains unclear in terms of agents used and duration of treatment. To treat acute exacerbation, the authors suggest using intravenous administration of two different classes of antibiotics. Maintenance antibiotics are administered to slow the decline in pulmonary function for P. aeruginosa chronic infection. The meaning of maintenance therapy has changed over time, beginning from intravenous quarterly anti- Pseudomonas antibiotics, irrespective of symptoms, to other strategies such as oral macrolides, ciprofloxacin or inhaled antibiotics (tobramycin and colistin). Aerosol delivery can provide a high concentration at the desired site with minimal absorption and therefore low risk of toxicity. There is scientific evidence that antibiotics are clinically effective in CF patients. Antibiotic selection should be based on periodic isolation and identification of pathogens and antimicrobial susceptibility.

Changes in cystic fibrosis airway microbial community associated with a severe decline in lung function

Cystic fibrosis (CF) is a genetic disease resulting in chronic polymicrobial infections of the airways and progressive decline in lung function. To gain insight into the underlying causes of severe lung diseases, we aimed at comparing the airway microbiota detected in sputum of CF patients with stable lung function (S) versus those with a substantial decline in lung function (SD). Microbiota composition was investigated by using culture-based and culture-independent methods, and by performing multivariate and statistical analyses. Culture-based methods identified some microbial species associated with a worse lung function, i.e. Pseudomonas aeruginosa, Rothia mucilaginosa, Streptococcus pneumoniae and Candida albicans, but only the presence of S. pneumoniae and R. mucilaginosa was found to be associated with increased severe decline in forced expiratory volume in 1 second (FEV1). Terminal-Restriction Fragment Length Polymorphism (T-RFLP) analysis revealed a higher bacterial diversity than that detected by culture-based methods. Molecular signatures with a statistically significant odds ratio for SD status were detected, and classified as Pseudomonas, Burkholderia and Shewanella, while for other Terminal Restriction Fragments (T-RFs) no species assignation was achieved. The analysis of T-RFLP data using ecological biodiversity indices showed reduced Evenness in SD patients compared to S ones, suggesting an impaired ecology of the bacterial community in SD patients. Statistically significant differences of the ecological biodiversity indices among the three sub-groups of FEV1 (normal/mild vs moderate vs severe) were also found, suggesting that the patients with moderate lung disease experienced changes in the airway assembly of taxa. Overall, changes in CF airway microbial community associated with a severe lung function decline were detected, allowing us to define some discriminatory species as well as some discriminatory T-RFs that represent good candidates for the development of predictive biomarkers of substantial decline in lung function.

Multiresistant non-fermentative Gram-negative bacteria in cystic fibrosis patients: the results of an Italian multicenter study

We carried out an epidemiological study on 2717 patients seen on a regular basis at Italian Cystic Fibrosis Centers with the aim of defining the prevalence of multiresistant Gram-negative strains in Italy. We found 272 multiresistant strains out of 1560 Gram-negative strains isolated in 1012 Italian cystic fibrosis patients. From our results in Italian cystic fibrosis patients we may conclude: (1)the beta-lactam antibiotics are moderately active; ceftazidime is the most efficacious even if 59.9% of multiresistant strains are not sensitive to this drug; (2)the aminoglycosides are poorly efficacious; 93% of multiresistant strains are resistant in vitro to tobramycin; and (3)the quinolones, notwithstanding their relatively recent introduction into clinical practice, have very poor activity against multiresistant strains, 89.7% of which are not sensitive.

Lactate in cystic fibrosis sputum

BACKGROUND Antibiotic therapy is thought to improve lung function in patients with cystic fibrosis (CF) by decreasing neutrophil-derived inflammation. We investigated the origin and clinical significance of lactate in the chronically inflamed CF lung. METHODS Lactate was measured in sputa of 18 exacerbated and 25 stable CF patients via spectrophotometry and gaschromatography. Lung function was assessed via spirometry. Seven patients with chronic obstructive pulmonary disease (COPD) and three patients with acute lung inflammation served as control groups. Neutrophil and bacterial lactate production was assessed under aerobic and anaerobic conditions. RESULTS In sputum specimens of patients with respiratory exacerbations lactate concentrations decreased significantly (p<0.005) from 3.4±2.3mmol/L to 1.4±1.4mmol/L after 2-3 weeks of intravenous antibiotics. Successful treatment was reflected in 16 patients (88.9%) by FVC increase associated with lactate decrease (p<0.05). In every single sputum lactate was detectable (3.0±3.1mmol/L, range 0.2-14.1mmol/L). Lactate was lower (1.6±0.8mmol/L) in sputa from seven COPD patients, and it was below the detection limit in three patients with acute lung inflammation. Neutrophil lactate production accumulated up to 10.5mmol/L after 4 days, whereas bacterial lactate production did not appear to contribute substantially to sputum lactate concentrations. CONCLUSIONS Successful antibiotic therapy is reflected by a decrease in lactate concentrations. Neutrophils are the most likely source for lactate in sputum of CF patients. Therefore lactate may be used to monitor responses to antibiotic therapy as an adjunct to lung function measurements.

Influenza A/H1N1 in patients with cystic fibrosis in Italy: a multicentre cohort study

The clinical consequences of influenza are severe in cystic fibrosis (CF), but the impact of A/H1N1 virus infection remains poorly defined.1 2 Pandemic influenza A/H1N1 started in Italy in September 2009 and CF patients were included among those at risk of complications and recommended to receive A/H1N1 vaccine. Better characterisation of the impact of influenza A/H1N1 in comparison with other flu-like illnesses in CF would provide a rational basis for antiviral treatment and vaccination strategies for the next flu season. Within the Italian Cystic Fibrosis Society, we sent a questionnaire to 30 centres to collect follow-up data for all patients with influenza-like symptoms consecutively seen between November 2009 and March 2010. Realtime RTPCR test was performed to define A/H1N1 status.3 Continuous variables are reported as medians, IQR (see online supplement for details of study methods). Nineteen centres reported data from 127 patients: 68 were ‘A/H1N1+ve’ and 59 were ‘A/H1N1–ve’ for the RT-PCR test. Symptom …